We are elucidating the genetic basis of leukemia formation by studying the Spontaneous dominant leukemia (Sdl) mouse mutant. The Sdl mutation arose in the germline of a male breeder in our colony, and results in highly penetrant lymphocytic leukemia early in life in mice that inherit the mutation. The germline inheritance combined with disease penetrance approaching 100% in this model provides a unique situation that allows the pre-neoplastic state in the hematopoietic system of these mice to be analyzed. Early molecular changes in cells that will undergo transformation in Sdl mice could serve as biomarkers for the presence of early disease in humans. We hypothesize that studying the Sdl mouse will identify genetic events involved in lymphocytic leukemia initiation and progression and will potentially identify a new human leukemia oncogene.